Abstract:

Despite recent negative results of the Gammaglobulin Alzheimer's Partnership (GAP) trial, the good tolerability
to intravenous immunoglobulin (IVIG) and its potential benefit for patient subpopulations have highlighted the importance
of understanding IVIG’s mechanism of action. IVIG contains antibodies to amyloid suggesting an amyloid clearance
mechanism. However, the suboptimal results of the amyloid immunotherapy trials suggest an additional mechanism.
Therefore, we tested whether IVIG alters the expression of tau neurofibrillary tangle (NFT)-like deposits within hippocampal
CA1 neurons of the 3xTg mouse model of AD. Three-month-old mice were treated intravenously with IVIG
(10%, 400 mg/kg) or placebo (10% BSA/saline) every two weeks for either three or six months. At sacrifice, plasma was
isolated for gene expression profiling and brains were processed for immunohistochemistry using the AT-180 antibody,
which recognizes hyperphosphorylated tau in NFTs. Stereologic analysis of CA1 neurons following three months of
treatment revealed no difference in AT-180+ neuron number but a significant 15-20% decrease in AT-180 intraneuronal
optical density with IVIG compared to placebo. By contrast, the number of AT-180+ CA1 neurons was reduced by 25-
30% following six months of IVIG treatment compared to placebo. Expression profiling studies showed that IVIG treatment
resulted in a significant 40-50% increase in plasma levels of genes regulating neuronal cytoskeletal plasticity function
and calcium-mediated signaling compared to placebo. Moreover, several transcripts encoding protein phosphatase
subunits were 40-50% higher in IVIG-treated mice. Hence, IVIG reduces hippocampal NFT pathology in the 3xTg mouse
through a mechanism that may involve preservation of neuronal plasticity and tau phosphorylation homeostasis.

Abstract:Despite recent negative results of the Gammaglobulin Alzheimer's Partnership (GAP) trial, the good tolerability
to intravenous immunoglobulin (IVIG) and its potential benefit for patient subpopulations have highlighted the importance
of understanding IVIG’s mechanism of action. IVIG contains antibodies to amyloid suggesting an amyloid clearance
mechanism. However, the suboptimal results of the amyloid immunotherapy trials suggest an additional mechanism.
Therefore, we tested whether IVIG alters the expression of tau neurofibrillary tangle (NFT)-like deposits within hippocampal
CA1 neurons of the 3xTg mouse model of AD. Three-month-old mice were treated intravenously with IVIG
(10%, 400 mg/kg) or placebo (10% BSA/saline) every two weeks for either three or six months. At sacrifice, plasma was
isolated for gene expression profiling and brains were processed for immunohistochemistry using the AT-180 antibody,
which recognizes hyperphosphorylated tau in NFTs. Stereologic analysis of CA1 neurons following three months of
treatment revealed no difference in AT-180+ neuron number but a significant 15-20% decrease in AT-180 intraneuronal
optical density with IVIG compared to placebo. By contrast, the number of AT-180+ CA1 neurons was reduced by 25-
30% following six months of IVIG treatment compared to placebo. Expression profiling studies showed that IVIG treatment
resulted in a significant 40-50% increase in plasma levels of genes regulating neuronal cytoskeletal plasticity function
and calcium-mediated signaling compared to placebo. Moreover, several transcripts encoding protein phosphatase
subunits were 40-50% higher in IVIG-treated mice. Hence, IVIG reduces hippocampal NFT pathology in the 3xTg mouse
through a mechanism that may involve preservation of neuronal plasticity and tau phosphorylation homeostasis.